“Pancreatic exocrine function tests” are useful for the diagnosis of pancreatic diseases such as chronic and acute pancreatitis and pancreatic cancer. It is also useful to assess the condition and the prognosis of patients and to manage the administration of medicine: The general descriptions are found in Arvanitakis and Cooke, Gastroenterology, 74:932 (1978); Niederau and Grendell, Gastroenterology, 88:1973 (1985); Goldberg, Bull. Mol. Biol. Med., 15:1 (1990); Lankisch, Int. J. Pancreatology, 14:9 (1993); Bank and Chow, Gastroenterologist, 2:224 (1994); and Steer et al., New Eng. J. Med., 332:1482 (1995).
The pancreatic exocrine function tests are roughly classified into intubation tests and tubeless tests. The intubation tests involve intubating a tube through the mouth to the duodenum to collect the duodenal juice. The secretin test is commonly used wherein secretin is intravenously administered to stimulate secretion of the pancreatic juice prior to the collection. This method is highly accurate since the amounts and components of the pancreatic juice are directly analyzed, and is regarded as the “gold standard” of pancreatic exocrine function test. However, this method can not be used repeatedly or used for screening purposes because of the very strong stress caused on the patients. It is only available at a relatively small number of clinical settings since the physician must be highly skilled. Further, since this method requires fluoroscopic tube placement during the collection of the duodenal juice, there is the problem of X ray exposure.
On the other hand, tubeless tests are easy to perform for estimating the pancreatic exocrine function without requiring intubation and the excreted amount of compounds produced by pancreatic exocrine enzymes or the excreted amount of the pancreatic exocrine enzymes per se is measured. At present, the following four methods are mainly used:    1. PFD test wherein a synthetic substrate BT-PABA (N-benzoyl-L-tyrosyl-p-aminobenzoic acid) for chymotrypsin secreted from the pancreas is orally administered and the amount of PABA (p-aminobenzoic acid), a product degradated by chymotrypsin, excreted into the urine is measured;    2. PLT test wherein a synthetic substrate FDL (fluorescein dilaurate) for cholesterol ester hydrolase, esterase, secreted from the pancreas is orally administered and the amount of the degradation product fluorescein excreted into the urine or the concentration thereof in the blood is measured;    3. Fecal chymotrypsin test wherein chymotrypsin in the feces is quantitatively determined; and    4. Fecal elastase test wherein elastase in the feces is quantitatively determined.
However, the sensitivity of any of these tests is too low to detect slight decreases in pancreatic exocrine function.
In order to solve this problem, many convenient pancreatic exocrine function tests have been searched for; 13C-breath tests have also been applied wherein a 13C-labeled compound is administered and an increase of the concentration of 13CO2 in the exhalation is measured. Examples of such 13C-breath tests are illustrated below:    1. 13C-breath test wherein a 13C-labeled lipid or mixed triglyceride, which is a substrate for lipase, is administered [Chen et al., J. Nuclear Med., 15:1125 (1974); Watkins et al., J. Lab. Clin. Med., 90:422 (1977); Ghoos et al., Digestion, 22:239 (1981); John, S G., Gastroenterology, 83:44 (1982); Watkins et al., Gastroenterology, 82:911 (1982); Benini et al., Digestion, 29:91 (1984); Jones et al., J. Lab. Clin. Med., 105:647 (1985); Knoblach et al., Monatsschr Kinderheilkd, 136:26 (1988); Vantrappen et al., Gastroenterology, 96:1126 (1989); Murphy et al., Arch. Disease in Childhood, 65:574 (1990); Kato et al., Am. J. Gastroenterol., 88:64 (1993); McClean et al., Arch. Disease in Childhood, 69:366 (1993); Jakobs et al., Eur. J. Pediatr., 156:S78 (1997); and Kalivianakis et al., Eur. J. Clin. Invest., 27:434 (1997)];    2. 13C-breath test wherein a 13C-labeled cholesterol ester, which is a substrate for cholesterol esterase, a lipase, is administered [Mundlos, et al., Pediatric Res., 22:257 (1987); Cole et al., Gastroenterology, 93:1372 (1987); and Mundlos et al., Gut, 31:1324 (1990)];    3. 13C-breath test wherein a 13C-labeled starch, which is a substrate for an amylase, is administered [Hiele et al., Gastroenterology, 96:503 (1989); Dewit et al., Pediatric Res., 32:45 (1992); and Z. Gastroenterol., 35:187 (1997)]; and    4. 13C-breath test wherein a 13C-enriched egg protein, which is a protein having a 13C-concentration increased up to 1.4 atm % from the natural abundance of 1.1 atm % by feeding a chicken with 13C-leucine, and which is a substrate for a protease, is administered [Y. Ghoos, 13CO2-Breath Tests at the laboratory “Digestion-Absorption”, University Hospital Gasthuisberg, Leuven, Belgium (1996)].
However, all these methods are of low sensitivity and time-consuming. Therefore, these methods have not been established in clinical fields.
As a highly sensitive pancreatic exocrine function test method that resolves the problems of the above-described convenient methods and 13C-breath tests, puts less burden on subjects, and gives accurate results immediately, a breath test using 13C-labeld peptides (13C-peptide breath test) has been proposed (Japanese Unexamined Patent Publication No. 2000-053697).
It is an object of the present invention to provide diagnostic agents for pancreatic exocrine function whose dose required for one test can be reduced without decreasing the degree of increase of 13C concentration in exhaled CO2 (Δ13C(‰)) in the 13C-peptide breath test which is a highly sensitive pancreatic exocrine function test that puts only small burden on subjects and which gives accurate results immediately.
It is another object of the present invention to provide novel compounds which may be used in pancreatic exocrine function tests using 13C-breath tests.